7alpha-acylthioprogesterones



United States Patent This invention relates to new chemical compounds, and, more particularly, to new'steroids of the formula wherein R is hydrogen, R is hydroxy, lower alkoxy, acyloxy, mercapto, or acylthio, or together R and R is oxo; and R" is acyl. The preferred acyl groups are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, such as the lower alkanoic acids '(e.g., acetic, propionic and hexanoic acid), the monocyclic aromatic carboxylic acids (e.g., benzoic acid), the monocyclic ar(alkanoic) acids (e.g., phenacetic and p-phenylpropionic acid), the lower alkenoic acids, the cycloalkanecarboxylic acids, and the cycloalkenecarboxylic acids.

The new steroids of this invention are physiologically active substances that possess progestational activity and hence may be administered parenterally in lieu of known progestational agents, such as progesterone, in the treatment of habitual abortion. The new steroids also possess anti-mineralocorticoid and anabolic activities.

The compounds of this invention are prepared by reacting either 4,6,l6 pregnatriene 3,20 dione or 4,6- pregnadiene-l6a-hydroxy-3,20-dione (or a 16-lower alkyl ether or a 16-ester thereof) with a thioacid. These starting steroids can be prepared as described in my application, Ser. No. 432,377, filed February 12, 1965. The preferred thioacids are those derived from hydrocarbon carboxylic acids of less than twelve carbon atoms, such as the thio derivatives of one of the acids mentioned hereinbefore. The reaction is preferably conducted at an elevated temperature using an excess of the thioacid. v

If 4,6,16-pregnatriene-3,20-dione is used as the steroid reactant, a 7a,16a-bisacetylthioprogesterone is obtained as the a product. If 4,6-pregnadiene-16ot-hydroxy-3,20- dione (or a 16-ether or ester thereof) is used as the reactant, the corresponding 7a-Inonoacylthio-l6a-hydroxy (or 16-ether or ester thereoD-progesterone is obtained as the product. To form the 7a-monoacylthio-16-ketoprogesterone product, the 7m acylthio 16oz hydroxyprogesterone is oxidized, as by treatment with chromic anhydride, to yield the corresponding 7a-acylthio-l6-ketoprogesterone.

The following examples illustrate the invention (all temperatures being in centigrade):

Example 1 .7ot,16a-bisacetylthioprogesterone A solution of 400 mg. of 6,16-tetra'dehydroprogesterone in 1.0 ml. of thioacetic acid is heated at 90 for two hours, then cooled, diluted with ether, and extracted with sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is plate chromatographed using alumina (activity V) as adsorbent and chloroform as the developing solvent. Detection of the band at R -0.2 by U.V., elution with ethyl acetate and crystallization of the residue after re- 3,309,385 Patented Mar. 14, 1967 moval of the solvent from acetone-hexane gives about mg. of 7a,16a-bisacetylthioprogesterone having a melting point about 182184;

[0.1% -27.5 (chloroform), xiii- 237 m (6,231,650);

x 5.90, 5.94, 5.15,.; 7, 4.28 (s, 4H),5.72 ((1 max O a l 9.5 c.p.s., 16B-H), 6.08'(m, 76-H), 7.65 (s, S ll-CH I? 7.74(s,SCOH3), 7.84 (s, 21CH 8.78 (s, Ill-CH 9.26 (s, 18-OH V Analysis.Calcd. for C H S O (462.65 )z C, 64.89; H, 7.40; S, 13.86. Found: C, 64.93; H, 7.32; S, 13.85. 1 Example 2.7a-acetylthi0-16a-hydroxyprogesterone Following the procedure of Example 1 but substituting 202.7 mg. of 6-dehydro-16ot-hydroxyprogesterone for the 6,16-tetradehydroprogesterone and using 0.4 ml. of thioacetic acid there is obtained about 98.3 mg. of 7aacetylthio 16a hydroxyprogesterone having a melting point about 180182,

xfig 238 m (5, 19,200),

I! 5.19 (m, 16BH), 6.08 (m, 7BH),7.66 (s, S-C--OH3). 7.83 (s, 21CH 8.78 (s, 19-oH3), 9.30 (5, 18-01-1 0.1 5 17.6 (chloroform), XNujol max.

Analysis.--Calcd. for C H O S (404.56): C, 68.27; H, 7.97. Found: C, 68.10; H, 7.76.

Example 3.-7a-acelylthi0-16ot-methoxyprogesterone Following the procedure of Example 2 but substituting 6-dehydro-16a-methoxyprogesterone for the 6-dehydro- 16a-hydr-oxyprogesterone, there is obtained 7a-acetylthio- 16a-methoxyprogesterone.

Example 4 .7 ot-acetyl th i0-] 6 -ket0pr0gester0ne Example 5.7ot-acetylthi0-16a-acet0xypr0gester0ne A solution of 50 mg. of 7a-acetylthio-16a-bydroxyprogesterone in 3 ml. of pyridine (dry) and 1 ml. of acetic anhydride is kept at room temperature for sixteen hours, then diluted with ice water and extracted with chloroform. The chloroform is washed with water and evaporated to dryness in vacuo. Crystallization of the residue gives 7a-acetylthio-16a-acetoxyprogesterone.

Example 6.7a,16a-bispr0pi0nylthioprogesterone Following the procedure of Example 1, but substituting thiopropionic acid for the thioacetic acid, 7a,16a-bispropionylthioprogesterone is obtained.

Similarly, by substituting any other thioacid for the thioacetic acid in the procedures of Examples 1, 2 and 3, thecorresponding thioesters are obtained.

The invention may be variously otherwise embodied within the scope of the appended claims.

a 3 4 What is claimed is: 5. 7oc-(lOW6I alkanoylthio)-16a-hydroxyprogesterone. 1. A compound of the formula 6. 7a-acetylthio-l6a-hydroxyprogesteronel 7. 7oc-(1OW6I alkanylthio)-16a-(lower alkoxy)progesterone.

5 8. 7a-acetylthi0-16a-methoxyprogesterone.

9. 7a-(lower alkanoylthio)-16-ketopr0gesterone. 10. 7a-acetylthio-16-ketoprogesterone. 11. 7oc-(1OW6I a1kanoy1thio)-16a-(lower alkan oyloxyy progesterone. 10 12. 7a-acetylthio-l6a-acetoxyprogesterone.

References Cited by the Examiner UNITED STATES PATENTS wherem R is hydrogen, R 1s selected from the group consisting of hydroxy, lower alkoxy, the acyloxy radical of 2,904,560 9/1959 Dodson et a1 -3 a hydrocarbon carboxylic acid of less than twelve carbon OTHER REFERENCES atoms, and the acylthio radical of a hydrocarbon thiocarboxylic acid of less than twelve carbon atoms, and Smlth et at Jour' M Chem" P- July together R and R is 0X0; and R" is the acyl radical of 1964,1313 531 and 532 rehed t gtglyirocarbon carboxyhc acld of less than twelve carbon ELBERT L. ROBERTS, Primary Examiner- 2. 7a,16oc-biS(l0W6r alkanoylthio) progesterone. LEWIS GOTTS, Examineh 3. 7a,16a-bisacetylthi0pr0gesterone. 4. 7a,16a-bispropionylthioprogesterone. HENRY FRENCH, Asslsmm E m 

1. A COMPOUND OF THE FORMULA 